Various contrast agents for use in diagnostic ultrasound, including echocardiography, have been described. A review of the subject is found in Ophir and Parker, Ultrasound in Med. & Biol. (1989), 15:319-333, although research has intensified since its publication.
In more recent years, agents which include gaseous microbubbles or microbubble precursors (as opposed to completely solid or liquid agents) have become the subject of great interest, since these agents take advantage of the relatively high echogenicity of gases versus liquids or solids.
To enhance the performance of microbubbles as ultrasound contrast agents, numerous approaches have been disclosed. These approaches are generally directed to methods by which either the persistence of the bubbles is increased or the bubble size population is optimized.
For example, such approaches include the use of solid particulates into which the bubbles are infused before use (e.g. U.S. Pat. No. 5,147,631), and the use of encapsulants or stabilizers for the microbubbles (such as human serum albumin, e.g. U.S. Pat. No. 4,718,433), each of which is incorporated by reference herein.
Another approach has been to identify compounds which, as gases, are relatively more persistent in blood than air (e.g. U.S. Pat. Nos. 5,393,524 and 5,409,688 and U.S. patent application Ser. No. 08/380,085, having the same assignee as the present application), and the use of a select number of such gases which are normally liquids at manufacturing temperatures but gases in the body in liquid-in-liquid dispersions (e.g. U.S. patent applications Ser. No. 08/008,172, Ser. No. 08/148,284 and Ser. No. 08/182,024, also assigned to the assignee of the present application) all of which are hereby incorporated by reference.
One method of producing microbubbles in a solution for use with ultrasound imaging is to disperse a gas in a liquid according to U.S. Pat. No. 4,832,941 by manual suspension, e.g., by spraying the liquid backwards and forwards in the gas atmosphere 25 times via a three-way tap.
Also, the use of ultrasound energy to promote the formation of microbubbles for use in ultrasound contrast is known both from U.S. Pat. No. 4,572,203 to Feinstein (prior to administration) and Molecular Biosystem's WO 94/28939 (in vivo, after administration), both of which are incorporated by reference herein. Neither of these methods, however, produce microbubbles capable of visualizing myocardial perfusion with a peripheral injection.
While such approaches have improved the quality and usefulness of diagnostic ultrasound contrast, further enhancements which provide even better images are desirable.